Malaria remains a significant threat to human health, with about 400 million people infected worldwide and about 2 million deaths per year, primarily children from tropical Africa. Disease control efforts have been limited by the lack of progress in vaccine development, drug resistance in the malaria parasite, and pesticide resistance in mosquito vectors. Transmission of the malaria parasite is totally dependent upon the availability of a competent mosquito vector. The potential for malaria and other arthropod-borne disease control by the genetic manipulation of the arthropod host has been recognized and advocated for at least three decades. Successful efforts to replace mosquito populations with individuals made resistant using transgenic procedures depend on three key elements: 1) efficient and stable resistance; and 3) development of delivery systems for introducing and promoting the spread of transgenic mosquitoes into natural populations (e.g., population replacement). The long-term objectives of this project are to develop methods to introduce mosquitoes genetically resistant to Plasmodium transmission into natural mosquito populations. Because stable transformation systems and some knowledge of endogenous meiotic drive systems for currently available for the mosquito Aedes aegypti, we proposes to initially develop and test the methodology for population replacement with this mosquito, and then apply these aims to Anopheles gambiae. The specific aims of this project are: 1) to examine the potential for using the Drosophila melanogaster segregation distorter (SD) gene complex to transform Ae. Aegypti; 2) to use a degenerate primer approach to isolate from Ae. Aegypti the orthologous SD sequence and to transform Ae. Aegypti the orthologous SD sequence and to transform Ae. Aegypti laboratory strains not expressing a meiotic drive phenotype; 3) to examine the potential for both the Drosophila and Ae. Aegypti Sd transgenes to distort segregation rations and drive a reporter gene in laboratory and natural populations of Ae. Aegypti; and 4) to use the system developed for Ae. Aegypti to transform and evaluate An. Gambiae.